Evaluation of the effect of endometrial scratch by hysteroscopic scissors on frozen embryo transfer outcomes: A historical cohort study

Abstract Background Endometrial scratch (ES) has been suggested to improve assisted reproductive techniques success rates by investigating implantation failure. Objective In this study, we evaluated the effect of ES on the outcomes of frozen embryo transfer (FET) in women with at least 2 failed embryo transfer cycles. Materials and Methods In this historical cohort study, medical data of 236 infertile women who underwent in-vitro fertilization-FET at Ebne-sina Infertility Center, Tehran, Iran, from January 2015-December 2021 was extracted from their medical records. Based on having ES before FET, they were assigned to either the scratch (n = 118) or the no-scratch group (n = 118). We compared these groups regarding pregnancy rates and outcomes. Results The demographic characteristics were similar in both groups regarding weight, body mass index, the number of previous embryo transfers, and the duration of infertility. However, the scratch group had a slightly higher mean age (32.31 vs. 29.96 yr, p < 0.001). No statistically significant difference was observed between groups regarding pregnancy rate (p = 0.89). No significant association was observed between scratch, infertility duration, the number of previous FET attempts, and the likelihood of pregnancy in a logistic regression model. No major complications were observed. Conclusion Hysteroscopic endometrial scratching with scissors probably has no effect on FET outcomes, including pregnancy or live birth rates.


Introduction
Based on archived reports from the Centers for Disease Control and Prevention, the number of performed assisted reproductive techniques (ART) cycles has doubled from 2009-2018 (1).
Despite the advancements in ART over the past decades, the pregnancy rate per embryo transfer remains below 35% (2).The growing demand for assisted reproduction underscores the importance of improving the ART success rate.An essential aspect of this pursuit is understanding endometrial tolerance during embryo implantation, a critical holdup in achieving a successful ART (3,4).In response to this need, a recent international consensus has emphasized the need for investigating implantation failure as a top research priority in medically assisted reproduction (5).
A study of endometrial gap junction proteins found that most women who failed in-vitro fertilization (IVF) and underwent repetitive endometrial sampling conceived in the following cycle.Building on this observation, they studied 134 cases with at least one IVF failure and reported that endometrial injury (pipelle biopsy) could double the IVF success rate (6).Since the publication of this study, endometrial scratch has gained considerable traction, prompting substantial debate within the scientific community.
Frozen embryo transfer (FET) is a widely employed ART procedure that transfers cryopreserved embryos into the uterus.2 decades following the inception of the first ES procedure, its advantages remain controversial.
While most studies worked on the effects of ES on fresh embryo transfer, we conducted this study to evaluate the effect of hysteroscopy and ES on the outcomes of FET in women with at least 2 failed embryo transfer cycles.

Inclusion criteria
1. Infertile women with a history of 2 unsuccessful embryo implantations (infertility was defined based on the history of at least 1 yr of regular and unprotected intercourse without a pregnancy).
4. Age < 39 yr at the time of the procedure.

Variables and measurements
Participants' data were collected from each

Hysteroscopy and endometrial scratch
The following method is used at the Ebnesina Infertility Center for endometrial scratch.
Women in the scratch group had undergone hysteroscopic ES using scissors one cycle before FET, between the 15 th and 20 th day of their menstrual cycle during the luteal phase.
The procedure was performed by an infertility specialist using hysteroscopy.Under general anesthesia and in a lithotomy position, a 4 mm lens was introduced to the uterus through the cervix.The uterine cavity was expanded by injecting a low-density liquid (normal saline) to visualize the uterine walls better.Finally, fine scratches on the endometrium were performed by hysteroscopic scissors.
On the 1 st -3 rd day of the cycle, all participants underwent an ultrasound to assess the thickness of the endometrium.The pregnancy beta-human chorionic gonadotropin test was performed 14 and 16 days after the FET.

Outcomes
A comprehensive comparison of the mentioned groups was conducted, focusing on both pregnancy rates and associated outcomes.

Statistical analysis
The

Results
Of the 420 initially selected cases, 236 women were included in the study.showing no significant association (Table II).(10,11).On the other hand, 2 recent systematic reviews suggested that ES (Pipelle biopsy or Novak curette) does not improve the pregnancy rates or outcomes (12,13).
Furthermore, a meta-analysis of 10 randomized controlled trials demonstrated that the beneficial effects of ES on pregnancy and live birth rates were only evident for cases with multiple previous IVF failures.Also, it concluded that the timing and technique of ES play a crucial role in determining its effectiveness on embyo implantation (14).
The variability in systematic review conclusions may be due to differences in inclusion criteria, quality assessment methods, publication bias, and author expertise and bias.Moreover, these studies did not consider the nuanced differences in the interventions.Furthermore, original studies on ES reported different results and were also linked with significant risks of bias (12).
There are several reasons for the discrepancies observed in the trial studies (4,(15)(16)(17)(18).Differences in the characteristics of the study population, the severity of the scratch, the phase of the menstrual cycle, and the appropriateness of the no-scratch group may contribute to these discrepancies.
Some studies have performed ES on women who had experienced one or 2 IVF failures (16,19), while some on the first cycle of IVF (17,20,21).
Additionally, although ES is reported to be most effective in the luteal phase (22), some studies have not reported the phase of the menstrual cycle for ES (23).
Recently, a randomized controlled trial reported that endometrial injury (with Pipelle) does not significantly improve the outcomes of FET in cases with repeated implantation failures (24).
Our study, which evaluated the efficacy of hysteroscopic scratch with scissors, has replicated these findings.Our findings in this matter align with other systematic review studies, indicating that ES does not lead to a higher incidence of pregnancy or live birth following FET (12,13).
Recent reviews report that clinical trials involving ES are susceptible to high bias levels (12,13,25).Such biases and pitfalls can potentially lead to misleading conclusions (26).Additionally, most studies fail to report essential outcomes such as live births and adverse events.Furthermore, it is important to note that the infertility-affected population is a vulnerable group that may be willing to try anything to achieve pregnancy.It is crucial to thoroughly evaluate any adjuvant therapies before incorporating them into routine practice.By doing so, we can ensure that individuals receive the most effective and evidence-based treatments available.

Limitations
Certain limitations arose from the retrospective nature of our study's design.Notably, the uneven distribution of older patients with extended infertility duration who received ES may have led to heterogeneity between the groups, potentially impacting our findings.Furthermore, due to the limited sample size, we were unable to conduct International Journal of Reproductive BioMedicine Endometrial scratch by scissors in FET subgroup analyses pertaining to infertility causes, failed IVF attempts, and diverse baseline ET.

Conclusion
To our knowledge, this is the first study reporting the effects of endometrial scratch with scissors on the outcomes of FET.Endometrial scratching probably is not associated with a higher rate of pregnancy and live birth in FETs.Also, the number of previous embryo transfers and infertility duration would not affect the outcome of FET.
Further, high-quality RCTs are recommended to address these issues.
couple's personalized infertility files according to the study checklist, including age, weight, BMI, infertility duration, infertility causes, preand post-FET treatments, ultrasound findings, and outcomes.The duration of infertility was determined based on the history of consistent and unprotected intercourse without resulting in a pregnancy.The infertility cause was evaluated by infertility fellows who examined the cases and categorized the causes as male infertility, female infertility (ovulatory dysfunction, tubal pathologies, and others), or both.Depending on whether the individuals had ES before FET, they were assigned to either the scratch (n = 118) or the no-scratch group (n = 118).

Table I .
Comparison of characteristics and outcomes of infertile women in groups (n = 118/each) *Data presented as Mean ± SD.Paired sample t test, **Data presented as median (Interquartile range), Mann-Whitney U test, ***Data presented as n (%), Pearson Chi-square, ****Data presented as n (%), Fisher's Exact test